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The Melanoma Inhibitory protein (MIA) was identified as an inhibitor of in vitro growth of malignant melanoma cells. The protein contains a SH3 domain. MIA acts as a potent tumor cell growth inhibitor for malignant melanoma cells and some other neuroectodermal tumors, including gliomas, in an autocrine fashion. In a study of human melanoma cell lines with different metastatic capacity MIA mRNA expression appeared to be inversely correlated with pigmentation. MIA has been shown to represent a very sensitive and specific serum marker for systemic malignant melanoma that might be useful for staging of primary melanomas, detection of progression from localized to metastatic disease during follow-up, and monitoring therapy of advanced melanomas.

The somatomedins, IGFs, comprise a family of peptides that play important roles in mammalian growth and development. IGF1 mediates many of the growth-promoting effects of GH. Early studies showed that GH did not directly stimulate the incorporation of sulfate into cartilage, but rather acted through a serum factor, termed 'sulfation factor,' which later became known as 'somatomedin. Three main somatomedins have been characterized: somatomedin C (IGF1), somatomedin A (IGF2; MIM 147470), and somatomedin B.

Chemokine (C-X-C motif) ligand 1 (CXCL1) is a small cytokine belonging to the CXC chemokine family that was previously called GRO1 oncogene, Neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MSGA-α). It is secreted by human melanoma cells, has mitogenic properties and is implicated in melanoma pathogenesis. CXCL1 is expressed by macrophages, neutrophils and epithelial cells, and has neutrophil chemoattractant activity. CXCL1 plays a role in spinal cord development by inhibiting the migration of oligodendrocyte precursors and is involved in the processes of angiogenesis, inflammation, wound healing, and tumorigenesis. This chemokine elicits its effects by signaling through the chemokine receptor CXCR2. The gene for CXCL1 is located on human chromosome 4 amongst genes for other CXC chemokines.

Fibroblast Growth Factors (FGFs) comprise a family of at least eighteen structurally realted proteins that are involved in a multitude of physiological and pathological cellular processes, including cell growth, differentation, angiogenesis, wound healing and tumorgenesis. The biological activities of the FGFs are mediated by a family if type I transmembrane tyrosine kinases which undergo dimerization and autophosphorylation after ligand binding. Four distinct genes encoding closely related FGF receptors, FGFR-1to -4 are known. Multiple forms of FGFR-1 to -3 are generated by alternative splicing of the mRNAs. A frequent splicing event involving FGFR-1 and -2 results in receptors containing all three Ig domains, referred to as the alpha isoform, or only IgII and IgIII, referred to as the ? isoform. Only the alpha isoform has been identified for FGFR-3 and FGFR-4. Additional splicing events for FGFR-1 to -3, involving the C-terminal half of the IgIII domain encoded by two mutually exclusive alternative exons, generate FGF receptors with alternative IgIII domains (IIIb and IIIc). A IIIa isoform which is a secreted FGF binding protein containing only the N-terminal half of the IgIII domain plus some intron sequences has also been reported for FGFR-1. Mutations in FGFR-1 to -3 have been found in patients with birth defects involving craniosynostosis.

Epidermal growth factor has a profound effect on the differentiation of specific cells in vivo and is a potent mitogenic factor for a variety of cultured cells of both ectodermal and mesodermal origin. The EGF precursor is believed to exist as a membrane-bound molecule which is proteolytically cleaved to generate the 53-amino acid peptide hormone that stimulates cells to divide.
EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture.

TRAF Family Member-Associated NFKB Activator (TANK) is located in the cytoplasm and binds Either TRAF1, TRAF2 or TRAF3. TANK is an inhibitor of TRAF function which regulates TRAF protein activity via sequestering TRAFs in a dormant position in the cytoplasm. Overexpression of TANK, inhibits TRAF2-mediated NF-Kappa-B activation signaled by CD40 and both TNF receptors and also inhibits LMP1-mediated NFkappa-B activation by blocking the connection of TRAF2 with LMP1.

GRB2 is widely expressed and binds the EGFR and contains one SH2 domain and two SH3 domains which form a complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. GRB2 is related to the Sem5 gene of C.elegans, which is takes part in the signal transduction pathway. GRB2 is an adaptor protein that provides an important link between cell surface growth factor receptors and the Ras signaling pathway. Inhibition of GRB2 activity damages developmental processes in a variety of organisms and blocks transformation and proliferation of different cell types.

Endothelial cells express three different vascular endothelial growth factor (VEGF) receptors, belonging to the family of receptor tyrosine kinases (RTKs). They are named VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), VEGFR-3 (Flt-4). Their expression is almost exclusively restricted to endothelial cells, but VEGFR-1 can also be found on monocytes, dendritic cells and on trophoblast cells. The flt-1 gene was first described in 1990. The receptor contains seven immunoglobulin-like extracellular domains, a single transmembrane region and an intracellular splited tyrosine kinase domain. Compared to VEGFR-2 the Flt-1 receptor has a higher affinity for VEGF but a weaker signaling activity. VEGFR-1 thus leads not to proliferation of endothelial cells, but mediates signals for differentiation. Interestingly a naturally occuring soluble variant of VEGFR-1 (sVEGFR-1) was found in HUVE supernatants in 1996, which is generated by alternative splicing of the flt-1 mRNA. The biological functions of sVEGFR-1 still are not clear, but it seems to be an endogenous regulator of angiogenesis, binding VEGF with the same affinity as the full-length receptor.

KIAA0101 is a PCNA-binding protein which performs as a regulator of DNA repair all through DNA replication. Subsequent to DNA mutilation, the collaboration with PCNA is interrupted, enabling the interaction between monoubiquitinated PCNA and the translesion DNA synthesis DNA polymerase eta (POLH) at stalled replisomes, assisting the bypass of replication-fork-blocking lesions. Additionally, KIAA0101 performs as a controller of centrosome number.

Upstream Transcription Factor 1 (USF1) belongs to the basic helix-loop-helix leucine zipper family, and functions as a cellular transcription factor. USF1 activates transcription via pyrimidine-rich initiator (Inr) elements and E-box motifs. The USF1 gene has been linked to familial combined hyperlipidemia (FCHL). USF1 is a transcription factor which binds to a symmetrical DNA sequence (E-boxes) (5'-CACGTG-3') found in a various viral and cellular promoters.

Mesoderm development candidate 2 (MESDC2) is required for formation of the primitive streak and mesoderm during embryogenesis. MESDC2 binds to the Wnt co-receptors LRP5 and LRP6 in the endoplasmic reticulum and is required for their proper folding and cell surface expression.

Human Factor IX also called Christmas-Factor is a glycoprotein, which is synthesized in the liver and belongs to the serine proteases system and is part of the S1 peptidase family.
Lack of Factor-IX causes Hemophilia-B meaning Christmas Disease. Factor-IX has a N-terminus region which contains 12xGla residues which asist the calcium dpendant binding of Factor-IX to the phospholipid surface. Factor-IX is activated by either factor XIa or the factor VIIa/tissue factor/phospholipid complex. Cleavage yields the intermediate IXa, which is subsequently converted to the fully active form IXab.
Factor-IX binds initially to exosites on the factor XIa heavy chain, followed by interaction at the active site with subsequent bond cleavage. Coagulation factor IX is activated by interaction with the erythrocyte membrane, causing intrinsic coagulation. Chaperones & lectins act simultaniously to guarantee the proper folding of Factor-IX and the retention of mutant molecules. Human Factor IX, activated by either the Contact or Tissue Factor Pathway, is responsible for the activation of Factor X to Xa.

Lipopolysaccharide-induced TNF-alpha factor (LITAF) is a small integral membrane protein of lysosome/late endosome. The expression of inflammatory cytokines such as TNF-alpha in Lipopolysaccharide-induced processes is mediated by LITAF. LITAF connects to STAT6B, which belongs to the STAT6 family forming a complex on the TNF-alpha promoter that modifies TNF activity. High levels of expression of LITAF mRNA are observed mostly in the placenta, peripheral blood leukocytes, lymph nodes and spleen.

CREB/ATF BZIP Transcription Factor, also known as CREBZF activates transcription strongly once bound to HCFC1. CREBZF suppresses the expression of HSV proteins in cells infected with the virus in a HCFC1-dependent manner. CREBZF suppresses the HCFC1-dependent transcriptional activation through CREB3 and reduces the quantity of CREB3 in the cell. In addition, CREBZF is capable to down-regulate expression of a few cellular genes in CREBZF-expressing cells.

Galectin-3 mediates with the alpha-3, beta-1 integrin the stimulation by cspg4 of endothelial cells migration. Galectin-3 plays an necessary part during the acquisition of vasculogenic mimicry and angiogenic properties associated with melanoma progression. LGALS3 overexpression is highly expressed in early stages of papillary carcinoma, and its expression intensity declines during tumor progression. Serum levels of LGALS3 are high in patients with thyroid malignancy but there is considerable overlap in serum LGALS3 concentrations between those with benign and malignant nodular thyroid disease. LGLAS3 takes part as an immune regulator to inhibit T-cell immune responses and promote tumor growth, as a result providing a new mechanism for tumor immune tolerance.

GABARAPL2 takes part in intra Golgi traffic and modulates intra Golgi transport by coupling between NSF activity and SNAREs activation. GABARAPL2 first stimulates the ATPase activity of NSF which in turn stimulates the association with GOSR1.

Fibroblast growth factors (FGFs) comprise a family of at least eighteen structurally related proteins that are involved in a multitude of physiological and pathological cellular processes, including cell growth, differentiation, angiogenesis, wound healing and tumorgenesis. The biological activities of the FGFs are mediated by a family of type I transmembrane tyrosine kinases which undergo dimerization and autophosphorylation after ligand binding. Four distinct genes encoding closely related FGF receptors, FGF R1 - 4, are known. All four genes for FGF Rs encode proteins with an N-terminal signal peptide, three immunoglobulin (Ig)-like domains, an acid-box region containing a run of acidic residues between the IgI and IgII domains, a transmembrane domain and the split tyrosine-kinase domain. Multiple forms of FGF R1 - 3 are generated by alternative splicing of the mRNAs. A frequent splicing event involving FGF R1 and 2 results in receptors containing all three Ig domains, referred to as the a isoform, or only IgII and IgIII, referred to as the b isoform. Only the a isoform has been identified for FGF R3 and FGF R4. Additional splicing events for FGF R1 - 3, involving the C-terminal half of the IgIII domain encoded by two mutually exclusive alternative exons, generate FGF receptors with alternative IgIII domains (IIIb and IIIc). A IIIa isoform which is a secreted FGF binding protein containing only the N-terminal half of the IgIII domain plus some intron sequences has also been reported for FGF R1. Mutations in FGF R1 - 3 have been found in patients with birth defects involving craniosynostosis. The complex patterns of expression of these receptors as well as the specificity of their interactions with the various FGF ligand family members are under investigation.

Chemokine (C-X-C motif) ligand 2 (CXCL2) is a small cytokine belonging to the CXC chemokine family that is also called macrophage inflammatory protein 2-alpha (MIP2-alpha), Growth-regulated protein beta (Gro-beta) and Gro oncogene-2 (Gro-2). CXCL2 is 90% identical in amino acid sequence as a related chemokine, CXCL1. This chemokine is secreted by monocytes and macrophages and is chemotactic for polymorphonuclear leukocytes and hematopoietic stem cells. The gene for CXCL2 is located on human chromosome 4 in a cluster of other CXC chemokines. CXCL2 mobilizes cells by interacting with a cell surface chemokine receptor called CXCR2.

Galectins are a family of animal lectins with an affinity for beta-galactosides. This family has at least 14 identified members. Galectins share similarities in the CRD (the carbohydrate recognition domain). Galectins are synthesized as cytosolic proteins. Though localized principally in the cytoplasm and lacking a classical signal peptide, galectins can also be stimulated to secretion by non-classical pathways or alternatively targeted to the nucleus. Galectins are involved in modulating cell-cell and cell-matrix interactions. Human Galectin-7 belongs to the prototypical Galectins containing a single CRD, which is initially identified in human epidermis as a monomer. The Galectin-7 expression is induced by tumor suppressor protein p53 and associated with apoptosis. Galectin-7 is a pro-apoptotic protein which functions intracellularlly upstream of JNK activation and mitochondrial cytochrome c release. The correlation of Galectin-7 with the UV-induced apoptosis of keratinocytes presents a critical mechanism in the maintenance of epidermal homeostasis. Human Galectin-7 is localized in both nucleus and cytoplasm.

Vascular endothelial growth factor is an important signaling protein involved in both vasculogenesis and angiogenesis. As its name implies, VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g. stimulation monocyte/ macrophagemigration, neurons, cancer cells, kidney epithelial cells ).VEGF mediates increased vascular permeability, induces angiogenesis, vasculogenesis and endothelial cell growth, promotes cell migration, and inhibits apoptosis. In vitro, VEGF has been shown to stimulate endothelial cell mitogenesisand cell migration. VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor. Elevated levels of this protein are linked to POEMS syndrome, also known as Crow-Fukase syndrome. Mutations in this gene have been associated with proliferative and nonproliferative diabetic retinopathy.

RANKL binds to tnfrsf11b/opg and to tnfrsf11a/rank. Osteoclast differentiation and activation factor. augments the ability of dendritic cells to stimulate naive t-cell proliferation. May be an important regulator of interactions between t-cells and dendritic cells and may play a role in the regulation of the t-cell-dependent immune response. sRANKL may also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy.

TGFBR2 is part of the Ser/Thr protein kinase family and the TGFB receptor subfamily. TGFBR2 is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with another receptor protein, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of a subset of genes related to cell proliferation. Mutations in TGFBR2 gene have been associated with Marfan syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. TGFBR2 expression is increased in oral squamous cell carcinoma cells. TGFBR2 attenuates the biological activities of TGF-beta in colorectal cancer. TGFBR2 expression is decreased by IL-1beta while inducing Sp3 via NFkappaB. TGFB2 and TGFBR2 are involved in the antiestrogenic activity of tamoxifen metabolites in breast cancer.

Gamma-glutamylaminecyclotransferase (A2LD1) is an enzyme which converts gamma-glutamylamines to free amines and 5-oxoproline. A2LD1 demonstrates high activity toward gamma-glutamyl-epsilon-lysine, derived from the breakdown of fibrin and other proteins cross-linked by transglutaminases. A2LD1 assists in the proteolytic degradation of crosslinked fibrin by breaking down isodipeptide L-gamma-glutamyl-L-epsilon-lysine, which is a byproduct of fibrin degradation. The reaction catalyzed by the A2LD1 produces 5-oxo-L-proline and a free alkylamine.